ELASTIN GENE MUTATIONS IN SKIN AND VASCULAR DISEASES

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The overall goal of this proposal is to understand the role of mutations in the elastin gene in the pathogenetics and pathobiology of two heritable diseases of elastic tissue, supravalcualar aortic stenosis (SVAS) and autosomal dominant cutis laxa (ADCL). Elastin is the major protein in elastic fibers and responsible for the recoil properties of all elastic tissues, including skin and blood vessels. Over the last few years, several investigators, including ourselves, have demonstrated that mutations in the elastin gene are responsible for two phenotypically distinct heritable disorders. SVAS is an autosomal dominant vascular disease characterized principally by arterial wall stenosis, with no obvious pulmonary or dermal phenotype. In contrast, ADCL is primarily a skin disorder characterized by inelastic skin with minimal vascular disease. Both disease have been shown recently to be due to mutations in the elastin gene. While it is not clear how mutations in the gene will result in two separate diseases, from preliminary results presented in the proposal, it seems that the nature of the mutations in the elastin gene will determine either a vascular or a dermal phenotype. The four specific aims that we have outlined in this proposal are intended to elucidate the detailed relationship between the type of mutations in the elastin gene and the influence of these mutations on both tissues morphogenesis, and elastin fiber assembly and elastin tissue function. Changes in elastin gene expression are a characteristic feature of many common elastic tissue disorders ranging from aortic aneurysms to keloids and we expect new insights from our proposed work on SVAS and ADCL to have a significant effect on a better understanding of the pathogenesis of these more common connective tissue disorders.